Transdermal Delivery of Medicinal Cetylated Fatty Esters using Phonophoresis or Iontophoresis

ABSTRACT

The use of phonophoresis or iontophoresis to enhance transdermal delivery of medicinal Cetylated fatty esters when applied in cream or gel compositions is disclosed. These compositions provide hydrophilic salt forms and penetration-enhancing vehicles that work in conjunction with phonophoresis or iontophoresis to increase the efficacy of the medicinal actives.

CROSS-REFERENCE TO RELATED APPLICATIONS

Not applicable

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not applicable

TECHNICAL FIELD

The present invention relates to compositions of creams, lotions andgels designed specifically to enhance delivery of medicinal Cetylatedfatty esters when either phonophoretic or iontophoretic techniques areutilized to facilitate the transdermal delivery of the medicament.

BACKGROUND OF INVENTION

The Applications of Cetylated Fatty Esters in Pain Management.

The medicinal utilization of Cetylated fatty acids were first describedin U.S. Pat. No. 4,049,824, Diehl, issued Sep. 20, 1977 and U.S. Pat.No. 4,113,881, Diehl, issued Sep. 12, 1978. These patents provideexamples for the oral utilization of cetyl myristoleate in effectiveamounts for the treatment of inflammatory rheumatoid arthritis inmammals. In U.S. Pat. No. 5,569,676, Diehl, issued Oct. 29, 1996extended treatment claims for cetyl myristoleate to treat osteoarthritsand to include topical and parenteral modes of delivery. U.S. Pat. No.6,417,227, Lord and Lytle, issued July, 2002 describes the use of cetylmyristoleate in the oral treatment of tendinitis, tenosynovitis,bursitis, chronic patellar tendinitis, Achilles tendinitis, fibrositis,inflammation of spine, colitis, bronchitis, polymyalagia rheumatic,Crohn's disease, primary biliary cirrhosis, pericarditis, ulcerativecolitis and Sjogren's syndrome. Cetyl myristoleate, as described in thispatent, when administrated in a dissolution resistant-coated capsule wasnoted to have therapeutic properties which could be applied to multiplecondition types having associated inflammation and immune mediated pain.U.S. Pat. No. 6,677,321, Levin, issued Jan. 13, 2004 extended the oraladministration of cetyl myristoleate for treating inflammatory diseases,when the cetyl myristoleate or one or more esters of unsaturated fattyacids and fatty alcohols are used in conjunction with at least onetetracycline compound, an NSAID, a COX-2 inhibitor, a corticosteroid,S-adenylmethionine or a synovial fluid supplement. For purposes of thisdisclosure, the Cetylated fatty esters are defined as a select group offatty acids that have been converted synthetically into cetyl esters,some with saturated and some unsaturated hydrocarbon chains, but withthe number of carbon atoms of these chains ranging from 10 to 18 or morein length. The composition of these select groupings often includes butis not limited to the inclusion of cetyl myristoleate.

The utilization of topical or oral applications of a selected group ofCetylated fatty esters has been described for treatment of periodontaldisease in U.S. Pat. No. 7,612,111, Spencer and Millsap, issued Nov. 3,2009 and U.S. Pat. No. 7,776,914, Spencer and Millsap, issued Aug. 17,2010. These patents also incorporate lecithin, olive oil and mixedtocopherols as part of their treatment compositions. U.S. Pat. No.7,772,279, Leonard and Simonton, issued Aug. 10, 2010 discloses the oraluse of a vegetable-derived, vegetable butter-based cetyl myristoleatefor treatment of musculoskeletal inflammation in animals, especiallyequines.

These patents are supported by numerous publications that definemedicinal properties of the cetyl fatty esters. Research has shown thatcertain Cetylated fatty esters act to relieve pain, improve jointmobility and return physical function due to affected joints in humansand in animal models. Other non-arthritic conditions that includemyofascial pain syndrome and sports-related pain injuries have alsodemonstrated therapeutic potential. For reference in defense of theseclaims the following are added herein: Hesslink et al., J Rheumatol, 29,pp. 1708-1812 (2002); Kraemer et al., J Rheumatol, 31, pp. 767-774(2004); Kraemer et al., J Strength Condit Res 19, pp. 475-480; Kraemeret al., J Strength Condit Res 19, pp. 115-121 (2005); Siemandi, TownsendLett Doctors & Patients, August/September, pp 58-63 (1997); Sharan etal., Manual Therapy, 14 (supp), pp. 51-53 (2009); Edwards, J NutrEnviron Med, pp. 105-111 (2007); Hunter et al., Pharm Res, 47, pp. 43-47(2003).

It is clear that the therapeutic utilization of Cetylated fatty estershas a history of at least two decades. The efficacy of these medicinalactives is associated with the need of multiple dosing applications inorder to get sufficient levels of absorption to obtain therapeuticresults. Oral absorption can be facilitated in capsule powders throughfine granulation and selected carrier excipients or in soft gel capsulesthrough the use of lipophilic oil carriers. The use of lecithin, oliveoils and other lipophilic compounds, for example, have been described inthe patent discussions of oral Cetylated fatty ester treatment, notedabove. The delivery of Cetylated fatty esters enter the skin and subepidermal layers, allowing them to be used widely in topicalformulations. The primary objective of this invention, however, was topossibly enhance the penetration of Cetylated fatty esters to greaterconcentrations using the disclosed gel, cream or lotion formulations inconjunction with phonophoresis or iontophoresis.

Transdermal Penetration Enhancement

Penetrant agents with lipophilic properties have been utilized for manyyears to enhance absorption of lipophilic drugs and are well known. Drugdelivery through the skin barrier is restricted primarily to passivediffusion in accordance to Fick's law (solute diffusivity is inverselyrelated to molecular size), due to the absence of active transport.

Fick's Law of Diffusion as it applies to drug transport across thestratum corneum can be stated as:

$J_{ss} = {{( \frac{D \cdot K_{{sc}\text{/}{veh}}}{h} ) \cdot C_{veh}} = {K_{p} \cdot C_{veh}}}$

where

-   -   J_(ss) is the steady-state flux across stratum corneum (mg cm⁻²        hr⁻²)    -   D is the diffusion coefficient or diffusivity of drug molecules        (cm⁻² hr⁻¹)    -   C_(veh) is the drug concentration gradient across the stratum        corneum (mg cm⁻³)    -   K_(sc/veh) is the partition coefficient of the drug between skin        and formulation medium,    -   K p is the formulation dependent permeability coefficient of the        drug, and    -   h is the thickness of the stratum corneum        (Drug lipophilicity has a major effect on K_(sc/veh)), and many        approaches to enhance drug delivery attempt to manipulate        K_(sc/veh) and C_(veh))

Numerous drug delivery formulations have been developed to enhancediffusion or to increase skin permeability or to both enhance diffusionand increase permeability. It is well known through bioavailabilitycomparisons of oral versus topical delivery of medicinal actives, thetopical delivery generally may provide systemic concentrations of 2-10%that of oral delivery.

The literature abounds with formulations designed to facilitatetransdermal delivery of various pharmaceutical actives. For a discussionof use of penetration enhancers in topical formulations the followingcitations are all hereby incorporated by reference: PERCUTANEOUSPENETRATION ENHANCERS (Eric W. Smith & Howard I. Maibach eds. 1995);Ghosh, T. K. et al., Pharmaceutical Technology, 17, p. 62 (1993); Ghosh,T. K. et al. Pharmaceutical Technology, 17, p. 68 (1993); Ghosh, T. K.et al. Pharmaceutical Technology, 17, p. 72 (1993).

U.S. Pat. No. 4,537,776, Cooper, issued Aug. 27, 1985, describes a meansby which pharmaceutically-active agents can be delivered transdermallyin greater concentrations through the use ofN-(2-hydroxyethyl)pyrrolidone and a “cell-envelope disordering compound”as penetrating agents. The enhancement potential through topical use ofpenetrating agents with pharmaceutical actives is described U.S. Pat.No. 3,989,816, Rhaadhyaksha (using 1-substituted azacycloheptan-2-onewith multiple types of actives), U.S. Pat. No. 4,132,781, Stoughton(using 2-pyrrolidone or an n-lower alkyl-2-pyrrolidone with antibioticsas actives), U.S. Pat. No. 4,017,641, DiGiulio (using 2-pyrrolidone and2.5% propylene glycol in skin conditioning compositions), U.S. Pat. No.4,343,709, Fawzi (using C5-C12 carbon length fatty acids withcorticosteroid actives), and U.S. Pat. No. 3,934,013, Poulsen (usingpropylene glycol, fatty alcohol and water with at least twocorticosteroids in the composition; the fatty alcohol being from 16-24carbon atoms, preferably a saturated, monohydric primary alcohol such ascetyl alcohol, stearyl alcohol or behenyl alcohol). These are given forexample, all of which are incorporated herein for reference.

A variety of lipophilic agent materials are described in European PatentNo. 43,738, Wickett et al., published Jan. 13, 1982. In addition,different types of surfactants (lipophilic and hydrophilic), incombinations with hydrophilic co-solvents may also enhancebioavailability depending on the physical properties of the drug ofinterest. Co-solvent examples would be propylene glycol and ethanol.Examples of anionic surfactants include sodium lauryl sulfate (SLS);example of cationic surfactants encompass cetyltrimethyl ammoniumbromide; nonionic surfactants and zwitterionic surfactant examples wouldinclude dodecyl betaine. U.S. Pat. No. 5,026,556, Drust et al, issuedJun. 25, 1991 describes the use of specific polar solvents (C3-C4 diols,C3-C6 triols and mixtures thereof) and polar lipid material (C8-C12fatty alcohol or fatty acid esters) for enhanced transdermal delivery ofbuprenorphine. U.S. Pat. No. 4,864,970, Patel and Chang, issued Sep. 5,1989 describes different formulation compositions specific for variousmedicinal actives which incorporate oleic acid, oleyl alcohol, glycerolmonoleate, glycerol dioleate, glycerol trioleate (and mixtures thereof)with inert diluents (water, propylene or polypropylene glycols andmineral oil being exemplary). It is evident from these and otherexamples that combinations, which make up delivery systems, must bedeveloped specifically for the actives being administered in order tooptimize sufficient flux of active through the skin, while alsominimizing side effects such as skin irritation. In general, increasedtissue wetness promotes transdermal delivery of both hydrophilic andlipophilic permeants.

Mechanical Enhancement of Transdermal Delivery of Pharmaceutical Drugs

However, regardless of the multiplicity of penetration enhancingformulations specifically designed to facilitate drug transdermaldelivery, mechanical methods of enhancing transdermal drug delivery, ingeneral, have been found to be superior to these passive methods ofdelivery. These properties have been found to be overcome to theaddition of the mechanical acceleration effects of ultrasound andiontophoresis, and these methods have the greatest interest for thisdisclosure. Other mechanical methods of enhancement and delivery ofpharmaceutical drugs transdermally include: physical therapy (e.g.,massage), electroporation, transdermal patches, implantable releasedevices/microchips, microneedle injection arrays, needleless injectiondevices, chemical or physical skin peels (microdermabrasion),magnetophoresis, and laser-radiation photomechanical wave devices. Theseother methods may form a basis for further disclosure at some othertime.

Phonophoresis (Sonophoresis)

For this disclosure, phonophoresis is the use of ultrasound (US) toenhance permeation for a topically applied therapeutic agent, wheneither applied simultaneously with therapeutic agent or with US as apretreatment step. It is closely associated with ultrasoundphysiotherapy, which is used in the treatment of soft-tissue injuries(such as tendinitis, tenosynovitis, epicondylitis, bursitis andosteoarthritis) but, in which topical application of a pharmaceuticaldrug is not being administered using ultrasound enhancement.Phonophoresis has been in practice since 1954 when this method wastherapeutically demonstrated with hydrocortisone topical administration.Alternating electrical current applied to a transducer with apiezoelectric crystal is used to produce the sonic waves. Treatmentduration, intensity and frequency of ultrasound utilization are keyparameters that affect percutaneous absorption, the latter having thegreatest effect. While frequencies between 20 kHz and 16 MHz have beendocumented as enhancing skin permeation, frequencies at the lower end ofthis range (<100 kHz) have been reported to provide the greatest effecton transdermal drug delivery. Through this approach macromolecules ofmolecular weight up to 48 kDa have been shown to be delivered throughtranscutaneous absorption. Diffusion of the topically applied drug canbe enhanced by both the thermal and non-thermal properties of theultrasonic sound waves. For example, heating can help dilate points ofentry (e.g., hair follicles and sweat glands), increase peripheralcirculation in the applied area and provide greater kinetic energy ofthe drug molecules being delivered. Both thermal and nonthermal effectscan increase cell permeability. Reported improvements in transportefficiency range from 2-5000 fold depending on molecular properties ofthe drug.

A coupling media, usually a gel or cream that has conductive properties,is used to eliminate the air layer space and thus increase the deliveryof ultrasonic energy to the skin and tissue. The composition of thecoupling media is of high importance since ultrasound waves encounteringa medium of dissimilar properties undergo refraction, reflection orabsorption, or all three properties. As examples for reference of thesynergistic interactions between chemical enhancers within couplingmedias and iontophoresis, ultrasound and electroporation, the review byMitragotri, Pharm. Research, 17, pp. 1354-1359 (2000) is hereinincorporated, as well as the following citations: Choi et al., Appl.Skin Physiol., 12, pp. 326-335 (1999); Le et al., Pharm. Res., 17,1151-1154 (2000); U.S. Pat. No. 5,947,921, Johnson et al., issued Sep.7, 1999; and U.S. Pat. No. 5,115,805, Bommannan et al., issued May 26,1993. U.S. Pat. No. 5,115,805 also discloses that the rates of drugpermeation through the skin is enhanced by using specific frequencies ofUS. Frequencies greater than 10 MHz were cited as providing enhancedpenetration.

Iontotophoresis

For this disclosure, iontophoresis (IS) is defined to be the method ofenhancing permeation for a topically applied therapeutic agent throughthe application either directly or indirectly of a low level electriccurrent. The amount of direct current is usually small (currently setlimit of 0.5 mA/cm²) and is applied through a drug containing electrodein skin contact and with a grounding electrode elsewhere on the body forcircuit completion. Alternatively, two electrode chambers, onecontaining the drug, can be placed side by side on the skin.

Enhancement mechanisms for iontophoresis are proposed to be one or morecombination of electroosmosis, electropertubation and electrorepulsion.Effective delivery of drugs is dependent of several parameters:electrode type, current intensity, pH of system, competitive ion effectand the types of permeants in the coupling media.

Bhatia et al., Journal of Controlled Release, 47, pp. 81-89 (1997)describe the use of enhancers (penetrant agents as 10% oleic acid incombination with ethanol or with propylene glycol) as important in orderto significantly enhance transdermal delivery of the active agent(luteinizing hormone releasing hormone). Clancy et al., InternationalJournal of Pharmaceutics, 105, pp. 47-56 (1994) is also which areincorporated herein for reference of the avidity of enhancers inincreasing iontophoresis efficacy. As a review of mechanical deliverymethods, including iontophoresis and ultrasound, Brown et al., Meth.Molec. Biol., 437, pp. 119-139 (2008) is incorporated herein as areference.

Polar molecules (with drugs having net negative charge being generallyfavored) are often shown to receive the greatest transdermal transportenhancement by this method. Highly lipophilic drugs, however, being morepolar neutral may show less enhancement through iontophoresis usage.Absorption is shown to decline linearly as alkyl chain length increases.However, Gangarosa et al. Journal of Pharmacology and ExperimentalTherapeutics, 212, pp. 377-381 (1980) have described enhanced nonionicmolecule transport due to the hydration of the stratum corneum withassociated sodium ion transfer (iontohydrokinesis; a mass transporteffect into the skin involving ions and water molecules). ELECTRICALLYASSISTED TRANSDERMAL AND TOPICAL DRUG DELIVERY (A. K. Banga, 1998) isherein incorporated as reference in regards to enhancement of polarneutral, molecule delivery by current-induced electroosmosis. It isclear that the composition of the cream or gel is critical forimprovement in transport when lipophilic drugs such as Cetylated fattyesters are used with iontophoretic methodologies.

For this disclosure, “transdermal” drug delivery is meant to be theadministration of a drug to the skin surface of an individual so thatthe drug passes through the skin tissue and into the individual's tissueor blood stream. The term “topical administration” is used in itsconventional sense to mean delivery of an active agent to a bodysurface, such as the skin or mucosa, as in, for example, topical drugadministration in the prevention or treatment of various skin disorders,arthritic conditions and musculocutaneous ailments, and the like.“Diffusion” is the movement of molecules through a domain, by randommolecular movement, from high concentrations to low concentration. “Flux(J_(ss))” is the amount of permeant crossing the skin or enteringsystemic circulation. This is measured as mass/area/time (or mg cm⁻²hr⁻¹). “Permeant” is selectively defined for this disclosure as themolecular species of disclosed interest that moves through or is movinginto the skin or tissue. “The molecular species of disclosed interest”in this disclosure are the Cetylated fatty esters.

BRIEF SUMMARY OF INVENTION

One of the objectives of the present invention is to provide a system bywhich specific medicinal agents, the molecular species of disclosedinterest, can be more efficiently delivered through topical applicationsinto the body. While several formulation enhancements have beendescribed previously, the utilization of phonophoresis and iontophoresisto enhance transdermal delivery of this group of molecules has not beendescribed. The need for such mechanical enhancements may not be readilyapparent because the Cetylated fatty esters are highly lipophilic, andthis is a favorable characteristic for transdermal delivery. A widevariety of long-chain fatty acids, for example, increase transdermaldelivery; the most popular is oleic acid. Aungst et al., Int. J.Pharmaceut., 33, pp. 225-234 describes the utilization of fatty acidsand fatty alcohols to enhance transdermal penetration of Naloxone.Unsaturated fatty acids and alcohols were more effective than saturatedones. It is logical that the Cetylated fatty acids also share some ofthese characteristics.

Further, the anti-inflammatory properties of these Cetylated moleculeshave been demonstrated through successful transdermal applications for anumber of inflammatory conditions. Even our own studies [Sharan et al.,Manual Therapy, 14 (supp), pp. S1-53 (2009)] suggest that effectivelevels of Cetylated fatty ester delivery could be demonstrated throughtopical cream applications. The need for further enhancement in deliverymay not necessarily be apparent, given the successful clinicalutilization of the topical treatments, but, given the possibleenhancements of phonophoresis seen clinically with other medicinalagents, the use of ultrasound was investigated as a possible source ofgreater enhancement. Some but not all molecules with similar mass orgreater have been shown to be given greatly enhanced transdermaldeliveries through the use of phonophoresis. Further consideration wasthat barrier functions of the skin restrict systemic deliveryconcentrations compared to oral delivery. Therefore, we developedformulations specifically for use with phonophoresis and iontophoresis.

In summary of these points, the presence of the cetyl chain greatlyincreases the lipophilic characteristics, due to the alkane cetyl chain.As we have disclosed previously in U.S. patent application Ser. No.12,608,963, Barathur and Bookout, submitted Oct. 29, 2009, the use ofCetylated fatty esters in combinations with chemical penetrants intopical delivery formulations greatly improves delivery of theseCetylated molecules and even to utilize them also with theseformulations as penetration facilitators for other molecules. It was onthe basis of these disclosures that further research was performed by usin order to find additional means of enhancing transdermal flux. Theresults from these studies helped us develop the disclosed invention ofusing specific formulations either in the form of a gel or a cream usingphonophoresis or iontophoresis.

One aspect of the present invention involves innovations whereby topicalformulations for the delivery of medicinal Cetylated fatty esters can becombined with to enhance the drug flux through the stratum corneum andinto the deeper layers of the underlying tissues. This is achievedthrough the effective use of Cetylated fatty esters with chemicalenhancer combinations in topical formulations with ultrasound. Theultrasound utilization is optimized in regards to modulated frequencies,amplitudes or phases or all three parameters. In this way the lag timeassociated with passive diffusion of the Cetylated fatty esters isreduced by utilizing the ultrasound energy to increase skin permeabilityand to provide improved flux through diffusion pathways.

In a further aspect of this invention, topical formulations weredeveloped and modified to enhance delivery of medicinal Cetylated fattyesters when combined with iontophoresis or sequential combinations ofboth iontophoresis and phonophoresis as an improved delivery system. Theuse of electrical current in this embodiment works in conjunction withelectrolytes and additional penetrant enhancers in the coupling media toopen molecular pathways for diffusion as well as hydration of thestratum corneum, allowing for the mass transport of solvent contents inthe process. Iontophoretic conditions have been optimized in regards toelectrolyte composition, pH and current parameters.

Still further aspects of this invention, are the formulations thatprovide improved delivery through the skin of the Cetylated fattyesters, while incorporating molecular enhancements that improve theefficiency of both ultra-sound and iontophoretic techniques. Thecomposition of the final formulations can be either that of a cream or agel. The chemical permeation enhancers are unique in their functionalcharacteristics. While other systems may be available for enhancement,the present combination for use with Cetylated fatty esters, inconjunction with phonophoresis and iontophoresis, has not beendescribed, to our knowledge. It was not clear at the time of thesediscoveries, if the use of these mechanical methods of enhancement wouldprovide improvement, as many reports have shown no improvement with somepharmaceutical drugs when these methods were used [for example,Williams, Ultrasonics, 28, pp. 137-141 (1990) is Incorporated herein asreference].

As examples of the driving forces utilized in this disclosure, theseinclude but are not limited to: acoustic energy through use ofultrasound; iontophoresis, electroporation, and electro-osmosis; heatwhere increase in temperature is utilized to enhance transport ofCetylated fatty esters; and pressure gradients where the apparatus usedhas capacity to provide either a positive or negative pressure gradientacross the area of application and this mechanical enhancement is used.

In a further aspect of this invention, this combination of Cetylatedfatty esters and chemical enhancement with phonophoresis oriontophoresis for delivery is novel for use in treatment applications ofvarious inflammatory conditions, such as osteoarthritis, rheumatoidarthritis, musculocutaneous injuries, tendinitis, Achilles tendinitis,tenosynovitis, bursitis, chronic patellar tendinitis, epicondylitis,periarticular soft tissue swelling, fibrositis, inflammation of spine,discogenic lower back pain, repetitive strain injuries, myofascial painsyndrome, fibromyalgia, polymyalagia rheumatic, peripheral neuropathies,herpetic neuropathies and Sjogren's syndrome. These applications arenovel in that the present invention provides a new approach forincreasing the effectiveness of treating these disorders.

The foregoing objects and advantages of the invention are illustrativeof those that can be achieved by the present invention and are notintended to be exhaustive or limiting of the possible advantages whichcan be realized. Thus, these and other objects and advantages of theinvention will be apparent from the description herein or can be learnedfrom practicing the invention, both as embodied herein or as modified inview of any variation which may be apparent to those skilled in the art.Accordingly, the present invention resides in the novel, formulationcompositions and utilization of mechanical enhancement systems as hereindescribed.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows treatment responses for the period from the initial visit(w0) though the 4^(th) week (w4). Scoring, as indicated by NPD-VAS AvgScore, was done using the neck pain and disability visual analogue scalefor data acquisition. Participants receiving only topical Cetylatedfatty acid cream applications are denoted in the figure responses as (

Cet FA alone). Those participants receiving topical Cetylated fatty acidcream plus therapeutic augmentation are denoted in the figure responsesas (

Cet FA+TherAug). The significance of these findings in relation to thisapplication are noted in Example 2, paragraph [059].

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a means of enhancing the rate ofpermeation of the Cetylated fatty esters through the skin by means ofcombining an enhancement media with ultrasound therapy. This inventionalso provides similar enhancement through the combined use withiontophoresis instead of ultrasound. The coupling media, in which themedicament Cetylated fatty esters are applied to the skin, is formulatedin such a way as to promote transdermal delivery as well as to improvesound or electrical conductance, and maximizing energy transmission tothe skin and deeper inner tissues.

The Disclosed Formulation

The Cetylated fatty esters for this disclosure have been defined as aselect group of fatty acids that have been converted synthetically intocetyl esters, some with saturated and some unsaturated hydrocarbonchains, but with the number of carbon atoms of these chains ranging from10 to 18 or more in length. The composition of these select groupingsoften includes but is not limited to the inclusion of cetyl oleate,cetyl palmitoleate and cetyl myristoleate. Other fatty acids, which canbe cetylated and utilized in the select groups, may be saturated, mono-to poly-unsaturated, or may contain functional groups such as methoxy-,amino- or ring structures. The preferred formulations contain aconcentration of 4-40% cetylated fatty esters. Most preferredconcentrations being 5-10%. The concentration of individual cetylatedfatty acids within typically ranges from 1-60% of the select group,depending on the cetylated molecule. Also, depending on the conditionbeing treated 3-12 cetylated fatty ester molecular forms may comprisethe select group.

The formulations of said coupling vehicle have compositions that includepolar emulsifiers, cream base, ionic salts, preservatives, antioxidants,fragrance and water. The coupling vehicle may also include otherchemical penetrant molecules.

Preferably, the polar solvent/emulsifier material in this invention ispropylene glycol. The polar solvent provides hygroscopic and miscibleproperties that allow solubility for the cetylated esters. This miscibleform of Cetylated fatty acids is used as a penetrating agent and onceintroduced the cetylated fatty esters by themselves serve as medicamentsin treatment of various types of pain described previously in thisdisclosure. A property of propylene glycol, critical for thisdisclosure, is its ability to hydrate the skin, bringing the flux ofwater molecules into the stratum corneum. Other polar solvents usedinstead of or in conjunction with propylene glycol include glycerol,ethylene glycol, 1,2,6-hexane triol, 1,2,4-butane triol, propyleneglycol ether of methyl glucose or sorbitol, PEG 40 hydrogenated casteroil, dimethicone copolyol, and polyethylene glycol (preferably, PEG 50,PEG 100 and PEG 500). One or more polar solvents may be used incombination in a final combined concentration of 5-30%.

The incorporation of menthol is disclosed for this invention as apreferred component. The concentration preferred is 1-5%. Its inclusionprovides vasodilatation properties that work in conjunction with eitherphonophoretic or iontophoretic enhancement to increase delivery of thecetylayed fatty esters and this vasodilator which has medicinalproperties of its own. Vasodilatation of the capillaries directlybeneath the basal layer shortens systemic delivery time and increasesconcentrations delivered in a shorter period of time. Menthol is alsotransdermally delivered in higher concentrations through use ofphonophoresis or iontophoresis. Another preferred component iseucalyptus oil (1-5%) which, like menthol, adds analgesic effects to themedicinal effects of the Cetylated fatty esters. Other envisioned andpreferred embodiments include ubiquinone, an inosine monophosphatedehydrogenase inhibitor, methyl salicylate, lavender oil, capsaicin andcamphor, together or separately.

Examples of antioxidants suitable for disclosed formulations includetocopherols, ascorbic acid and its esters, alpha lipoic acid, thiourea,and chelating agents like EDTA and citric acid.

Preferably, the pH of the formulations range from 4.0 to 8.0. The rangeof ph 4.0 to 6.8 is more preferable, but the most preferred range is pH5.0 to 6.6. For utilization in the iontophoretic applications the ionicstrength is modified to optimize conductance. Compounds useful as pHregulators include, but are not limited to sodium citrate, sodiumacrylate, phosphate buffers, sodium or potassium hydroxide, glycerolbuffers and triethanolamine. Sodium chloride or potassium chloride arepreferred regulators for adjustment in conductance as needed.

The thickening agents composing the formulation base include but are notlimited to carbomer polymers (Carbopol 940 NF, Carbopol 934 NF, CarbopolAqua CC,), hydroxycellulose, polyvinylacetate, polybutylacrylate, PEG100 stearate, polymethylacrylate, polydimethylsiloxane, hydrogels (e.g.,high molecular weight polyvinylpyrrolidone, oligomeric polyethyleneoxide, or a mixture thereof) and organogels. PEG 40 hydrogenated casteroil or polyethoxylated castor oil may be used for proper composition inconjunction with the thickening agents. Other suitable components suchas alcohol may be included up to 10%. Preferred alcohols are ethanol,2-propanol and methanol. Water is preferably present at concentrationsup to 80%. There are two preferred viscosities for application: Low(40-50 Kcps) for cream and gel and Medium (70-80 Kcps) for gel.

Example of preservatives include, but are not limited to benzalkoniumchloride, cetrimide, benzethonium chloride, imidizolidinyl urea, benzylalcohol, isopropyl alcohol, triclosan, hydantoin derivatives,phenyoxyethol, imidazolidinylurea and parabens. Preferably thepreservative is methyl paraben, propyl paraben, or a mixture thereof.

For phonophoretic application, a cream, gel or lotion is a preferredtype of coupling media formulation. For iontophoretic application, a gelis a preferred type of coupling media formulation. For use with drugelectrodes having a delivery matrix pad, the formulation withoutthickening agents is preferred. However, these preferences do notrestrict the type of agent for each application.

Phonophoresis

“Ultrasound” is ultrasonic radiation of a frequency above 20,000 Hz. Thepresent invention employs frequencies in the range of about 20-2,500kHz, preferably in the range of 500-1,500 kHz. Preferred intensity isless than 5.0 W cm⁻² and especially preferred at 0.01 to 5 W cm⁻². Withcontinuous beam intensity the preferred range is 0.5-2.5 W cm⁻². The useof continuous ultrasound provides thermal heating, which is furtherconducive for enhanced delivery of Cetylated fatty esters. It is alsothe continuous mode that is preferred when utilized with conditions, inwhich movement is restricted. Use of discontinuous pulsing reducesheating effects when needed while still facilitating diffusion throughthe other properties of ultrasound application, which are thought toinclude oscillating of particles in the tissue and in the drug deliverycomposition, decreasing of membrane potential and increased cellpermeability, increasing ion conductance and alterations in theskin-lipid structure. Discontinuous pulsing may be preferred for acutepain and inflammation. For these conditions a preferred pulsing cycle is1 MHz frequency with 3 pulse/cycle using a 3.3 msec pulse during, 10msec periods.

It is emphasized that these ranges are intended to be merelyillustrative of preferred embodiment; in some cases, higher or lowerfrequencies may be used. Ultrasound may be pulsed or continuous, butpreferably continuous when used at lower frequencies. For continuousmode ultrasound, the preferred frequency is 1 MHz with an intensity of1.0 W·cm⁻². At high frequencies, pulsed application is generallypreferred to enable generated heat dissipation.

The duration of ultrasound treatment may vary with the condition andseverity, preferably 5-45 min in either continuous or pulse mode, morepreferably 5-30 min, most preferred 5-10 minutes. Preferredphonophoresis treatment frequency recommended for this invention is 3-4times per week for 3 weeks. This may be repeated as needed.

Prior treatment before ultrasound or with simultaneous application ofdrug in coupling media with ultrasound is envisioned as effectiveapproaches in this invention. It is, therefore, effective when theaffected area on the individual is first treated with ultrasound,providing the effects of ultrasound directly to that area, then followedby application of the coupling vehicle containing Cetylated fatty estersand allowing for enhanced delivery and further treatment through thereapplication of ultrasound.

“An ultrasound device” includes one or more ultrasound devices necessaryto carry out the present invention and “administration methods” denoteone or more methods currently known or become known after the reading ofthis disclosure.

Iontophoresis

The present invention in another embodiment accomplishes trandermalenhancement through the use of current applied through the vehiclecoupling media in intensities equal to or less than 0.5 mA cm⁻². Thepreferred range is 0.2-0.5 mA cm⁻². The preferred electrode for drugdelivery is positive; however, the use of drug delivery using thenegative electrode may also be possible due to the somewhat neutralproperties of the Cetylated fatty esters. Current levels may range from0.5 to 5 mA depending on electrode area size. Drug electrodes withdelivery capacity of 1 to 3 cc are preferred depending on the size ofarea affected on the individual and the severity. Maximum preferreddosage is 40 to 80 mA-minutes. The use of iontophoretic devices withramp up and ramp down capacity is preferred to provide 30 second rampingat 0.006 to 0.01 mA cm⁻².

In an extension of this embodiment, when iontophoresis is used toenhance delivery of the permeant of interest, the subsequent applicationof ultrasound to the same applied area further increases the effects ofthe delivery.

“An iontophoresis device” includes one or more iontophoretic devicesnecessary to carry out the present invention and “administrationmethods” denote one or more methods currently known or become knownafter the reading of this disclosure.

Example 1

The following are representative of compositions which can be formulatedwithin the scope of this invention. They are for illustrative purposeonly and are not intended to define the scope of the invention.Formulations are prepared through combining components with compatiblemixing properties at elevated temperatures and then mixing componentstogether while lowering the temperature, followed by adding thosecomponents with greater thermolability. All compositions are presentedby % weight per volume.

COMPONENT FORMULATION A FORMULATION B FORMULATION C FORMULATION DCetylated Fatty Esters  5-10% 15-20%  5-10%  5-10% Menthol 1-5% 1-5%1-5% 1-5% Eucalyptus Oil   1% —   1% — Polar Solvents  12%  15%   8% 10% Disodium EDTA 0.1% 0.1% 0.1% 0.1% Carbomer 940 NF 0.7% 0.2% 0.5% —PEG 100 Stearate — — — 0.5% Hydroxycellulose — — —   1% Anti-oxidant0.5-2%   0.5-2%   0.5-2%   0.5-2%   Cremophore RH 40   1% — 0.5% —Fragrance 0.02-1%   — 0.02-1%   — Purified Water q.s. q.s. q.s. q.s.Preservative   0.1-0.2.2%   0.1-0.2.2%   0.1-0.2.2%   0.1-0.2.2% SodiumHydroxide To pH 5.5 To pH 5.0 To pH 6.5 — Triethanolamine — — — To pH5.8 Electrolyte Salts As needed for As needed for As needed for Asneeded for optimal optimal optimal optimal conductance conductanceconductance conductance Use Indicated with X X X Phonophoresis UseIndicated with X X X X Iontophoresis

Example 2

An assessment was made in order to measure what enhancements could bederived from combining topical delivery of Cetylated fatty esters withphysical therapeutic enhancing systems. Patients with myofascial painsyndrome of the neck and shoulders, with at least 2 trigger points(MTrPs), were randomized into 2 groups: a) topical Cetylated fattyesters cream application only (n=35), and b) topical Cetylated fattyesters cream application plus physical augmentation (n=37). Therapeuticsessions providing physical augmentation were given twice per week ifdesignated and topical cream was applied liberally twice daily ifdesignated. This baseline comparison study followed patients for 4 weekswith 3 assessment visits.

Cetylated fatty esters cream formulation contained several cetylatedfatty esters and 1.5% w/w menthol in a cream base (with creamcomposition based on Formula C in Example 1, having a pH of 6.5).Placebo cream had the same composition but without cetylated fattyesters.

Data was collected through the following sources: therapist work up,tenderness to palpation, algometer readings and for each trigger point,Cervical Range of Motion measurements (CROM^()), and writtenparticipant responses to three evaluators, namely: a) neck pain anddisability visual analogue scale (NPDVAS), b) Neck Disability Index(NDI), and c) the 36-item short-form health survey (SF36).

Physical augmentation plus the topical cetylated fatty estersapplications provided the fastest and most effective treatment modalityof the study. Efficacy results allowed for the following rankings—a) forpain (NPDVAS and SF36 pain index): cetylated fatty esters topical plusphysical augmentation was more effective that cetylated fatty esterstopical alone; b) for neck disability (NDI): cetylated fatty esterstopical plus physical augmentation was more effective that cetylatedfatty esters topical alone; c) for life quality (SF36 total index):cetylated fatty esters topical plus physical augmentation was moreeffective that cetylated fatty esters topical alone; d) for SF36(physical activity index): Cetylated fatty esters topical plus physicalaugmentation was more effective that cetylated fatty esters topicalalone; e) for range of motion (CROM): Cetylated fatty esters topicalplus physical augmentation was again more effective than cetylated fattyesters topical alone. Topical administration of cetylated fatty estersresulted in a significant reduction in pain and neck disability by theend of the 4 week period. However, cetylated fatty esters topicaltherapy was significantly improved when combined with therapeuticaugmentation.

When combined with physical augmentation, improvements of patientconditions were better in most measurements than physical augmentationwith a placebo cream application.

Example 3

Results from therapeutic augmentation led to evaluation of usingultrasound to augment topical cetylated fatty esters delivery. A gelbase similar to that in example 1 (formulation C), containing 5-10%cetylated fatty esters was used in treatments of: myofascial painsyndrome, fibromyalgia, tennis elbow, wrist tendinitis, supraspinatustendinitis, low back pain, knee osteoarthritis, sprains, jointinflammation after post operative joint stiffness, and golfer's elbow(n=40) with ultrasound delivery augmentation (1 MHz at 1.0 W cm⁻², withtreatment duration of 7 minutes). Probe position through the gel allowedfor a 0.2 and 1.5 mm distance from the skin. The rise in temperature atthe application site during the 7 minute period of continuous ultrasoundaveraged about 3° C. Decreases in treatment response time andimprovements in degree of response were noted compared to topicalcetylated fatty esters treatment alone. While in the previous example,the average response time for significant improvements in pain reductiontook approximately 2 weeks (cetylated fatty esters plus therapeuticaugmentation), the average response time with phonophoretic augmentationof topical cetylated fatty esters delivery was reduced to 4-7 days.

Example 4

A group of 11 patients with osteoarthritis of lower back or knee weretreated with phonophoresis (1 MHz at 1.5 W cm⁻², with treatment sequenceduration of 10 minutes continuous pulse, followed by 3 minutes of nopulse, followed by another 10 minutes of continuous pulse) withapplication of the cetylated fatty esters in the coupling media (aformulation like the of Formulation A in Example 1) to the general areaover the affected joint(s). With daily treatment, most noted significantimprovements within 3-10 days. These results were much sooner thanexpected.

Example 5

The cream version (a Formulation A of Example 1) of this invention hasbeen clinically tested further with phonphoresis with an ultrasoundmachines at 1 mZh (1 W cm⁻²; continuous, with duration 7 minutes pertreatment) in several hundred patients in clinical settings. Patientconditions included knee pain from Osteoarthritis, discogenic back pain,tendinitis, bursitis, fibromyalgia, carpal tunnel syndrome and otherpain disorders. The vast majority of these patients noted significantimprovements in pain within 3-7 days. Similarly, a gel version of thisinvention (formula A of Example 1) has been clinically tested with anultrasound machine set at 1 mHz (1-2 W cm⁻²; continuous, with durationsranging from 5-10 minutes per treatment) a number of patients. Patientconditions included knee pain from osteoarthritis, discogenic back pain,tendinitis, bursitis, fibromyalgia, carpal tunnel syndrome, repetitivestrain injuries and other pain disorders. Further, a lotion version ofthis invention (formula B of Example 1) is proposed to be used withultrasound set at 1 mHz. Patient conditions will include knee pain fromosteoarthritis, back pain, tendinitis, bursitis, fibromyalgia, carpaltunnel syndrome, repetitive strain injuries and other pain disorders.While different responses were noted with the different conditions,severity and individuals, all responses were favorable, similar to otherexamples given herein.

Example 6

Formulations for effective use with iontophoresis have been developed.Those with best efficacy are indicated in Example 1, formulations B andD. Iontophoretic settings chosen was 4 mA for total delivery of 20mA-min and applying cream using the positive electrode. This combinationis given as an example and does not limit the use of other treatmentcombinations.

Modifications and variations of the present invention will be obvious tothose skilled in the art from the foregoing detailed description, andare intended to come within the scope of the appended claims.

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1. A composition for the transdermal delivery of medicinally-activeCetylated fatty esters, which provides enhanced delivery when combinedwith phonophoretic or ionophoretic techniques.
 2. The compositionaccording to claim 1 containing a vehicle base of either a gel, lotionor cream property.
 3. The composition of Cetylated fatty estersaccording to claim 1 being a 4-40% concentration of a select group of 3or more Cetylated esters of fatty acids, some with saturated and someunsaturated hydrocarbon branched or unbranched chains, and with thenumber of carbon atoms of fatty acids selected ranging from 10 to 18 ormore in length.
 4. The composition according to claim 1 where the polarsolvent at a 5-30% concentration is at least one of the following:propylene glycol, polypropylene glycol, glycerol, ethylene glycol,1,2,6-hexane triol, 1,2,4-butane triol, propylene glycol ether of methylglucose or sorbitol, PEG 40 hydrogenated caster oil, dimethiconecopolyol, and polyethylene glycol (preferably, PEG 50, PEG 100 and PEG500).
 5. The composition according to claim 1 where menthol is includedin a concentration of 1-20%.
 6. The composition according to claim 1where the pH range is from 4.0 to 8.0.
 7. The phonophoretic techniquesaccording to claim 1 in which ultrasound, with either continuous ordiscontinuous pulsing, in the range of 20-2,500 kHz is used to enhancethe delivery the Cetylated molecules indicated in claim
 3. 8. Thephonophoretic techniques in claim 7 where beam intensity is less than5.0 W cm⁻²
 9. The combination of the composition of claims 1, 2, 3 and4, whereby, when combined with the delivery of claim 7 and claim 8,greatly enhances penetration 200% or more than the composition ofcetylated fatty esters used alone without phonophoresis.
 10. Theionophoretic techniques according to claim 1 in which transdermal fluxfor Cetylated fatty esters is facilitated through the use ofelectro-osmosis, as generated by low level electric current applied tothe skin.
 11. The iontophoretic techniques according to claim 10 inwhich current intensity ranges from 0.5-20 mA.
 12. The medicinalapplications for use of the composition according to claim 1 being thatof osteoarthritis, rheumatoid arthritis, inflammation of spine,discogenic back pain and polymyalagia rheumatic.
 13. The medicinalapplications for use of the composition according to claim 1 being thatof musculocutaneous injuries, tendinitis, Achilles tendinitis,tenosynovitis, bursitis, chronic patellar tendinitis, epicondylitis,periarticular soft tissue swelling, repetitive strain injuries, andmyofascial pain syndrome.
 14. The medicinal applications for use of thecomposition according to claim 1 being that of fibrositis, fibromyalgia,peripheral neuropathies, herpetic neuropathy and Sjogren's syndrome.